The most important mechanism of microbial resistance to β-lactam antibiotics is the bacterial production of β-lactamases, enzymes that hydrolytically destroy β-lactam antibiotics, such as penicillins and cephalosporins. This type of resistance can be transferred horizontally by plasmids that are capable of rapidly spreading the resistance, not only to other members of the same strain, but even to other species. Due to such rapid gene transfer, a patient can become infected with different organisms, each possessing the same β-lactamase.
β-lactamase enzymes have been organized into four molecular classes: A, B, C and D based on amino acid sequence. Class A, includes RTEM and the β-lactamase of Staphylococcus aureus, class C, includes the lactamase derived from P99 Enterobacter cloacae, and class D are serine hydrolases. Class A enzymes have a molecular weight of about 29 kDa and preferentially hydrolyze penicillins. The class B lactamases are metalloenzymes and have a broader substrate profile than the proteins in the other classes. Class C enzymes include the chromosomal cephalosporinases of gram-negative bacteria and have molecular weights of approximately 39 kDa. The recently recognized class D enzymes exhibit a unique substrate profile that differs significantly from the profile of both class A and class C enzymes.
One strategy for overcoming this rapidly evolving bacterial resistance is the synthesis and administration of β-lactamase inhibitors. Frequently, β-lactamase inhibitors do not possess antibiotic activity themselves and are thus administered together with an antibiotic. One example of such a synergistic mixture is “AUGMENTIN” (a registered trademark of Smithkline Beecham Inc), which contains the antibiotic amoxicillin and the β-lactamase inhibitor, clavulanic acid.
Unfortunately, current commercial inhibitors target only class A β-lactamases, which have historically been the most clinically relevant. Recently, however, there has been an increase in the number of infections possessing class B, C, and D β-lactamases. In fact, some microorganisms produce both class B and class A enzymes, potentially making it possible for the metallolactamases to actually protect the serine enzymes. Useful inhibitors of class B, C, and D enzymes are, at present, not available clinically. In particular, inhibitors which solely target class B may not be commercially viable, since the relatively low current rate of metallolactamase-mediated infections will not justify the considerable cost of development.